Phosphatidylinositol 3,4,5-triphosphate (Ptdlns(3,4,5)-P3), the end product of phosphatidylinositol 3-kinase (P13-K) phosphorylation of polyphosphoinositides, has recently been identified in islets. A rapid, transient increase in PtdIns (3,4,5)P3 levels, which peaks with the acute insulin response, can be induced by insulin secretagogues. We have analyzed the regulatory subunit of P13-K, p85a, as a candidate gene for the high prevalence of NIDDM in Pima Indians. A polymorphism at nucleotide 1020 (G--<A) which alters a Met to an lle at codon 326 in p85a was determined to be more frequent in Pimas (allelic frequency = 0.25) as compared to Caucasians (allelic frequency in CEPH = 0.17 and in Danes = 0.16). Analysis of this polymorphism in 950 full-blooded Pimas determined that the prevalence of NIDDM in individuals with the variant lle/lle genotype was lower (50%) compared to the prevalence in those with the Met/Met genotype (60%). This difference was due to the females in the study sample (n=550) where the prevalence of NIDDM in women with the common Met/Met genotype was higher (p<0.02). This difference was not observed in 400 Pima men (prevalence of NIDDM = 54% for both lle/lle and Met/Met). Women with the variant lle/lle genotype also had significantly higher acute insulin responses compared to women with the Met/Met genotype (p<0.008), which is consistent with the higher prevalence of diabetes observed in the latter group. These results have been published (Diabetes 47, 1998), but the associations were not strong enough to warrant further investigation into the pathophysiology of this variation. Therefore, this project is terminated.